1. Field of the Invention
The present invention relates to certain aminoalkyl naphthalenediol derivatives that enhance natural human host resistance to viral infectious organisms. The derivatives are administered prophylactically to human individuals whose resistance to infection has been compromised by chemotherapy, surgery, burns, other forms of severe stress, and, in particular, AIDS-related virus.
2. Brief Description of Disclosures in the Art
Recent medical progress has resulted in beneficial therapy for many patients with conditions which were previously untreatable. As a result of both the extended survival of such patients and the therapeutic methods employed, today's physicians are more frequently encountering the patient who is at great risk of developing opportunistic infection because his host defenses have been impaired in particular by an AIDS-related virus.
Seven years ago few had ever heard of acquired immunedeficiency syndrome, or AIDS. This puzzling affliction, then seen in only a small number of young, homosexual men, was something new and unnamed. Today, it's hard to find anyone in the U.S. who hasn't heard of AIDS, the disease that can debilitate and then kill its victim with horrific swiftness.
AIDS has come to be recognized as a public health emergency. More than 27,700 American men, women, and children have been stricken by it; the death toll is 16,000 and rising. The U.S. Public Health Service predicts that by the end of 1991 more than 179,000 persons will have succumbed to the disease.
Thus far, there is no cure for AIDS.
Technically, Acquired ImmuneDeficiency Syndrome (AIDS) is a transmissible deficiency of cellular immunity characterized by opportunistic infections and certain rare malignancies. The dominant risk groups for AIDS include homosexually active males, intravenous drug abusers, recipients of transfusions and blood products, and the heterosexual partners and children of high-risk individuals, suggesting the involvement of an infectious agent transmitted through intimate contact or blood products.
Recent evidence indicates that the infectious agent responsible for disease transmission is a novel lymphotropic retrovirus, currently designated HIV (human immunodeficiency virus) and also known as lymphadenopathy-associated virus (LAV) (Barre-Sinoussi et al., Science 220: 868 (1983)). Similar viruses have been reported by other scientific groups (Popovic et al., Science 224: 497 (1984); Levy et al. Science 225: 840 (1984)) and designated human T-cell lymphotropic virus type III (HTLV-III), AIDS-associated retrovirus (ARV), or immunedeficiency-associated virus (IDAV). Still more recent data indicates that LAV, HTLV-III, ARV and IDAV share several important characteristics, including substantial nucleotide homology (Wain-Hobson et al., Cell 40: 9 (1985); Muesing et al., Nature 313: 450 (1985); Sanchez-Pescador et al., Science 227: 484 (1985)), and should be considered isolates of the same virus, although there is a likelihood that strain-to-strain variations among the viral isolates will exist. In addition to exhibiting substantial nucleotide homology, the isolates are similar with respect to morphology, cytopathology, requirements for optimum reverse transcriptase activity, and at least some antigenic properties (Levy, supra: Schupbach et al., Science 224: 503 (1984). The above materials are hereby incorporated by reference to characterize the phrase "AIDS-related virus".
In the field of immunology, it has been found that certain compounds including, bacterial cell wall peptidoglycans (in particular, muramyl dipeptide and its derivatives) lipopolysaccharide, glucans, ubiquinones, bestatin, amphotericin B, tuftsin, thymic hormones, interferon, polyadenylic acid complexes, pyran copolymers, levamisole, methisoprinol and the like, although not specifically therapeutic against a particular pathogen, act in such a manner to improve the host resistance to infection by bacteria, virus, fungus, or parasite in a human host whose immunological system has been compromised.
In the past, bacterial cell wall products (e.g., BCG, C. parvum, etc.), as well as plant polysaccharides (e.g., lentinan, krestin, etc.), have been employed to stimulate the natural host resistance. These agents all suffer from undesirable toxic side effects, such as granulomatous inflammation, etc. Presumably the development of inflammation enhances the mobilization and activation of inflammatory cells as well as augmentation of the immune response (adjuvant effect).
In light of the above discussion, new classes of organic compounds are constantly being evaluated and screened to see if they possess host resistance enhancement activity, particularly in an immunocompromised host as a result of an AIDS-related virus.
One class of compounds recently of interest are the aminoalkyl naphthalenediols.
In the art, naphthalenediols are described in U.S. Pat. No. 3,009,912; British Pat. No. 790,203; British Pat. No. 790,202; and in Brit. J. Pharmacol. 12(1957) p. 171, "Anti-Malarial Activity of Hydroxy-Substituted Naphthalene Compounds" by W. M. Duffin and I. M. Rollo. The above compounds are described as being active as antimalarial agents against blood forms of Plasmodium species. However, there is no specific suggestion as to their use as host resistance enhancement agents.
At present, there is no effective host resistance enhancer on the market that does not possess the ability to cause intense granulomatous inflammation. The use of host resistance compounds that cause inflammation is not desirable.
For reviews, see (1) J. Kralovec, "Synthetic Immunostimulants in Antitumor Therapy," Drugs of the Future 8(1983)615; (2) J. W. Hadden, "Immunomodulators in the Immunotherapy of Cancer and Other Diseases," Trends in Pharmacological Sciences, (1982)191; (3) E. Arrigoni-Martelli, "Developments in Drugs Enhancing the Immune Response," Meth. Find. Exptl. Clin. Pharmacol, 3(1981)247; and (4) J. Drews, "The Experimental and Clinical Use of Immunomodulating Drugs in the Prophylaxis and Treatment of Infections," Infection, 12(1984)157.
Therefore, it is an object of this invention to provide compositions containing host resistance enhancement agents that are safe and effective against viral infection and whose therapeutic mechanism does not involve significant granulomatous inflammation.
Furthermore, it is also an object of this invention to provide a method of treatment for enhancing host resistance against opportunistic infection in humans who are immunologically compromised as a result of an AIDS-related virus.
Further provided is a pharmaceutical composition comprising said agent and an approved AIDS therapeutic drug, e.g. azidothymidine (AZT).